Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/17378
Title: BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux.
Authors: Reljic, Boris;Conos, Stephanie;Lee, Erinna F;Garnier, Jean-Marc;Dong, Li;Lessene, Guillaume;Fairlie, W Douglas;Vaux, David L;Lindqvist, Lisa M
Affiliation: Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
Structural Biology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Department of Chemistry and Physics, La Trobe Institute for Molecular Science, Melbourne, Victoria, Australia
Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia
Issue Date: 2-Jul-2016
EDate: 2016
Citation: Autophagy 2016; 12(7): 1083-1093
Abstract: Inhibition of prosurvival BCL2 family members can induce autophagy, but the mechanism is controversial. We have provided genetic evidence that BCL2 family members block autophagy by inhibiting BAX and BAK1, but others have proposed they instead inhibit BECN1. Here we confirm that small molecule BH3 mimetics can induce BAX- and BAK1-independent MAP1LC3B/LC3B lipidation, but this only occurred at concentrations far greater than required to induce apoptosis and dissociate canonical BH3 domain-containing proteins that bind more tightly than BECN1. Because high concentrations of a less-active enantiomer of ABT-263 also induced BAX- and BAK1-independent LC3B lipidation, induction of this marker of autophagy appears to be an off-target effect. Indeed, robust autophagic flux was not induced by BH3 mimetic compounds in the absence of BAX and BAK1. Therefore at concentrations that are on target and achievable in vivo, BH3 mimetics only induce autophagy in a BAX- and BAK1-dependent manner.
URI: http://ahro.austin.org.au/austinjspui/handle/1/17378
DOI: 10.1080/15548627.2016.1179406
PubMed URL: 27172402
Type: Journal Article
Subjects: ABT-199
ABT-263
ABT-737
BCL2
BECN1
autophagy
Appears in Collections:Journal articles

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